Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis

Summary. The limitations of liver biopsy (invasive procedure, sampling errors, inter‐observer variability and nondynamic fibrosis evaluation) have stimulated the search for noninvasive approaches for the assessment of liver fibrosis in patients with viral hepatitis. A variety of methods including the measurement of liver stiffness, using transient elastography, and serum markers, ranging from routine laboratory tests to more complex algorithms or indices combining the results of panels of markers, have been proposed. Among serum indices, Fibrotest has been the most extensively studied and validated. Transient elastography appears as a promising method but has been mostly validated in chronic hepatitis C with performance equivalent to that of serum markers for the diagnosis of significant fibrosis. The combination of both approaches as first‐line assessment of liver fibrosis could avoid the performance of liver biopsy in the majority of patients with chronic hepatitis C, a strategy that deserves further evaluation in patients with hepatitis B or HIV‐HCV coinfection. Transient elastography also appears to be an excellent tool for early detection of cirrhosis and may have prognostic value in this setting. Guidelines are now awaited for the use of noninvasive methods in clinical practice.     

Noninvasive methods to assess liver disease in patients with hepatitis B or C

The prognosis and management of patients with chronic viral hepatitis B and C depend on the amount and progression of liver fibrosis and the risk for cirrhosis. Liver biopsy, traditionally considered to be the reference standard for staging of fibrosis, has been challenged over the past decade by the development of noninvasive methodologies. These methods rely on distinct but complementary approaches: a biologic approach, which quantifies serum levels of biomarkers of fibrosis, and a physical approach, which measures liver stiffness by ultrasound or magnetic resonance elastography. Noninvasive methods were initially studied and validated in patients with chronic hepatitis C but are now used increasingly for patients with hepatitis B, reducing the need for liver biopsy analysis. We review the advantages and limitations of the noninvasive methods used to manage patients with chronic viral hepatitis B or C infection.     

Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C

Liver fibrosis is the main predictor of the progression of chronic hepatitis C, and its assessment by liver biopsy (LB) can help determine therapy. However, biopsy is an invasive procedure with several limitations. A new, noninvasive medical device based on transient elastography has been designed to measure liver stiffness. The aim of this study was to investigate the use of liver stiffness measurement (LSM) in the evaluation of liver fibrosis in patients with chronic hepatitis C. We prospectively enrolled 327 patients with chronic hepatitis C in a multicenter study. Patients underwent LB and LSM. METAVIR liver fibrosis stages were assessed on biopsy specimens by 2 pathologists. LSM was performed by transient elastography. Efficiency of LSM and optimal cutoff values for fibrosis stage assessment were determined by a receiver-operating characteristics (ROC) curve analysis and cross-validated by the jack-knife method. LSM was well correlated with fibrosis stage (Kendall correlation coefficient: 0.55; P < .0001). The areas under ROC curves were 0.79 (95% CI, 0.73-0.84) for F > or =2, 0.91 (0.87-0.96) for F > or =3, and 0.97 (0.93-1) for F=4; for larger biopsies, these values were, respectively, 0.81, 0.95, and 0.99. Optimal stiffness cutoff values of 8.7 and 14.5 kPa showed F > or =2 and F=4, respectively. In conclusion, noninvasive assessment of liver stiffness with transient elastography appears as a reliable tool to detect significant fibrosis or cirrhosis in patients with chronic hepatitis C.     

Assessment of fibrosis and cirrhosis in liver biopsies: an update

The liver biopsy specimen represents valuable material for the assessment of fibrosis and cirrhosis. Despite limitations related to sampling and interpretation, histologic examination remains the gold standard for staging chronic liver diseases. Hepatic fibrosis is currently viewed as a dynamic process that may often regress after successful treatment of chronic liver diseases. Even the excess fibrous tissue of cirrhotic livers may sometimes regress over time. Distinguishing between the amount of hepatic fibrosis and the disease stage is important for the assessment of the effects of antifibrotic treatments. Recent studies suggest that the proportion of the liver biopsy specimen occupied by collagen is correlated with the hepatic venous pressure gradient in liver transplant recipients with hepatitis C virus infection, with or without cirrhosis, and represents a predictor of clinical decompensation. This parameter has also been found to correlate with liver stiffness measurements of patients with chronic viral hepatitis obtained by transient elastography. Therefore, quantitative assessment of hepatic fibrosis in liver biopsy specimens holds promise as a prognostic marker, and as a means to validate noninvasive markers of fibrosis.     

Acoustic radiation force impulse imaging for non‐invasive assessment of liver fibrosis in chronic hepatitis B

Acoustic radiation force impulse (ARFI) imaging is a novel ultrasound‐based elastography method that is integrated in a conventional ultrasound machine. It might provide an alternative method to transient elastography for the noninvasive assessment of liver fibrosis. While previous studies have shown comparable diagnostic accuracy of ARFI to transient elastography in chronic hepatitis C, the aim of the present prospective multicenter study was to evaluate ARFI for the assessment of liver fibrosis in chronic hepatitis B. ARFI imaging involves the mechanical excitation of tissue using short‐duration acoustic pulses to generate localized displacements in tissue. The displacements result in shear‐wave propagation which is tracked using ultrasonic, correlation‐based methods and recorded in m/s. In the present international prospective study, patients infected with chronic hepatitis B received ARFI imaging, blood tests and if available transient elastography. The results were compared to liver biopsy as reference method analysed by a central pathologist. In 92 of 114 patients, a comparison of ARFI with transient elastography was possible. ARFI imaging and transient elastography correlated significantly with histological fibrosis stage. The diagnostic accuracy expressed as areas under ROC curves for ARFI imaging and transient elastography was 0.75 and 0.83 for the diagnosis of significant fibrosis (F ≥ 2), 0.93 and 0.94 for the diagnosis of severe fibrosis (F ≥ 3), and 0.97 and 0.93 for the diagnosis of liver cirrhosis, respectively. No significant difference was found between ARFI and transient elastography. ARFI imaging is a reliable ultrasound‐based method for the assessment of advanced stages of liver fibrosis in chronic hepatitis B.     

The role of liver biopsy in chronic hepatitis C

Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide, affecting 175 million people globally. Over 80% of acutely infected patients go on to develop chronicity, but only 20% to 25% will develop end-stage liver disease and its complications. The sequelae of HCV-induced chronic liver disease accounts for 8,000 to 10,000 deaths annually in the United States and is currently the leading indication for liver transplantation. To date, there are no accurate noninvasive markers of disease activity and fibrosis. Liver biopsy is indicated to exclude other forms of liver pathologies and to establish the stage of liver disease. In this study, the role of liver biopsy in chronic hepatitis C was evaluated. Additionally, we calculated a discriminant score to predict cirrhosis in chronic hepatitis C infection. Our results showed that additional diagnoses or unsuspected diagnoses are less frequent than clinicians' suspected. We confirmed that the discriminant score for predicting cirrhosis is inferior to liver biopsy. In conclusion, the majority of patients with chronic hepatitis C will require a liver biopsy, which has an important implication on staging of the liver disease, prognosis, and possibly further management options.     

Elastography for Longitudinal Assessment of Liver Fibrosis after Antiviral Therapy: A Review

Chronic hepatitis B or C viral infection is a common cause of liver cirrhosis and hepatocellular carcinoma. Fibrosis regression can be achieved after long-term antiviral therapy (AVT). Monitoring of dynamic changes in liver fibrosis after treatment is essential for establishing prognosis and formulation of a follow-up surveillance program. Routine surveillance of fibrosis after AVT by liver biopsy, the gold standard for fibrosis assessment, is hindered by its invasive nature, sampling error and observer variability. Elastography is a noninvasive quantitative alternative that has been widely used and validated for the staging of liver fibrosis prior to treatment. Recently, increasing research interest has been focused on the role of elastography in longitudinal assessment of liver fibrosis after AVT. In this review, the basic principles, acquisition techniques, diagnostic performances, and strengths and limitations of ultrasound elastography and magnetic resonance elastography are presented. Emerging evidence regarding the use of elastography techniques for the monitoring of liver fibrosis after AVT is summarized. Current challenges and future directions are also discussed, designed to optimize the application of these techniques in clinical practice.     

Noninvasive assessment of liver fibrosis in chronic hepatitis C infection

Hepatic fibrogenesis is a dynamic process that reflects a balance between matrix synthesis and degradation. An accurate determination of hepatic fibrosis is important in determining prognosis, requirement for therapy, and disease progression in chronic hepatitis C infection. Histologic assessment relies on a liver biopsy, an invasive procedure associated with sampling error and inaccurate staging that provides only a semiquantitative and static measure of fibrosis and inflammatory activity. Several noninvasive tools initially developed and validated in chronic hepatitis C patients are now being applied to other chronic liver disease states. These noninvasive approaches include simple and complex serum biochemical marker algorithms, radiologic methods such as elastography, and emerging genomics and proteomics technologies. In the future, the combination of these diagnostic modalities likely will provide a more accurate and reliable measure of disease severity in chronic liver disease patients.     

Acoustic radiation force imaging sonoelastography for noninvasive staging of liver fibrosis

AIM: To investigate the diagnostic accuracy of acoustic radiation force impulse (ARFI) imaging as a noninvasive method for the assessment of liver fibrosis in chronic hepatitis C (CHC) patients.METHODS: We performed a prospective blind comparison of ARFI elastography, APRI index and FibroMax in a consecutive series of patients who underwent liver biopsy for CHC in University Hospital Bucharest. Histopathological staging of liver fibrosis according to the METAVIR scoring system served as the reference. A total of 74 patients underwent ARFI elastography, APRI index, FibroMax and successful liver biopsy.RESULTS: The noninvasive tests had a good correlation with the liver biopsy results. The most powerful test in predicting fibrosis was ARFI elastography. The diagnostic accuracy of ARFI elastography, expressed as area under receiver operating characteristic curve (AUROC) had a validity of 90.2% (95% CI AUROC =0.831-0.972, P < 0.001) for the diagnosis of significant fibrosis (F ≥ 2). ARFI sonoelastography predicted even better F3 or F4 fibrosis (AUROC = 0.993, 95% CI =0.979-1).CONCLUSION: ARFI elastography had very good accuracy for the assessment of liver fibrosis and was superior to other noninvasive methods (APRI Index,FibroMax) for staging liver fibrosis.     

Noninvasive diagnosis of hepatic fibrosis in chronic hepatitis C

Assessment of hepatic fibrosis is important for determining prognosis,guiding management decisions,and monitoring disease. Histological evaluation of liver biopsy specimens is currently considered the reference test for staging hepatic fibrosis. Since liver biopsy carries a small but significant risk,noninvasive tests to assess hepatic fibrosis are desirable. This editorial gives an overview on noninvasive methods currently available to determine hepatic fibrosis and their diagnostic accuracy for predicting significant fibrosis and cirrhosis in chronic hepatitis C. Based on available data,the performance of simple tests derived from routine laboratory parameters appears to be similar to that of more complex and expensive fibrosis panels. Transient elastography seems more accurate than blood tests for diagnosing cirrhosis.     

Chronic hepatitis C and liver fibrosis

Chronic infection with hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality worldwide and predisposes to liver fibrosis and end-stage liver complications. Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, and is considered as a wound healing response to chronic liver injury. Its staging is critical for the management and prognosis of chronic hepatitis C (CHC) patients, whose number is expected to rise over the next decades, posing a major health care challenge. This review provides a brief update on HCV epidemiology, summarizes basic mechanistic concepts of HCV-dependent liver fibrogenesis, and discusses methods for assessment of liver fibrosis that are routinely used in clinical practice. Liver biopsy was until recently considered as the gold standard to diagnose and stage liver fibrosis. However, its invasiveness and drawbacks led to the development of non-invasive methods, which include serum biomarkers, transient elastography and combination algorithms. Clinical studies with CHC patients demonstrated that non-invasive methods are in most cases accurate for diagnosis and for monitoring liver disease complications. Moreover, they have a high prognostic value and are cost-effective. Non-invasive methods for assessment of liver fibrosis are gradually being incorporated into new guidelines and are becoming standard of care, which significantly reduces the need for liver biopsy.     

瞬时弹性成像技术在慢性乙型肝炎中的应用进展

肝活检是诊断肝脏疾病的金标准,胃镜是诊断食管胃静脉曲张的金标准;但二者均为有创检查,因此应用受限。近年来瞬时弹性成像技术作为无创检测,临床已经广泛采用。介绍了瞬时弹性成像技术在慢性乙型肝炎患者肝纤维化、肝脂肪变、肝硬化及肝癌等方面的最新进展。未来可在乙型肝炎肝硬化和肝癌早期联合诊疗方面进行更多研究。     

Noninvasive models for assessment of liver fibrosis in patients with chronic hepatitis B virus infection

There are approximately 240 million patients with chronic hepatitis B virus (HBV) infection worldwide. Up to 40% of HBV-infected patients can progress to liver cirrhosis, hepatocellular carcinoma or chronic end-stage liver disease during their lifetime. This, in turn, is responsible for around 650000 deaths annually worldwide. Repeated hepatitis flares may increase the progression of liver fibrosis, making the accurate diagnosis of the stage of liver fibrosis critical in order to make antiviral therapeutic decisions for HBV-infected patients. Liver biopsy remains the “gold standard” for diagnosing liver fibrosis. However, this technique has recently been challenged by the development of several novel noninvasive tests to evaluate liver fibrosis, including serum markers, combined models and imaging techniques. In addition, the cost and accessibility of imaging techniques have been suggested as additional limitations for invasive assessment of liver fibrosis in developing countries. Therefore, a noninvasive assessment model has been suggested to evaluate liver fibrosis, specifically in HBV-infected patients, owing to its high applicability, inter-laboratory reproducibility, wide availability for repeated assays and reasonable cost. The current review aims to present the status of knowledge in this new and exciting field, and to highlight the key points in HBV-infected patients for clinicians.     

How far is noninvasive assessment of liver fibrosis from replacing liver biopsy in hepatitis C?

Chronic hepatitis C represents a major cause of progressive liver disease that can eventually evolve into cirrhosis and its end-stage complications. Formation and accumulation of fibrosis in the liver is the common pathway that leads to evolutive liver disease. Precise staging of liver fibrosis is essential for patient management in clinical practice because the presence of bridging fibrosis represents a strong indication for antiviral therapy, while cirrhosis requires a specific follow-up. Liver biopsy has always represented the standard of reference for assessment of hepatic fibrosis, but it has limitations: it is invasive, costly and prone to sampling errors. Recently, blood markers and instrumental methods have been proposed for the noninvasive assessment of liver fibrosis in hepatitis C. However, international guidelines do not recommend the widespread use of noninvasive methods for liver fibrosis in clinical practice. This is because of, in some cases, unsatisfactory accuracy and incomplete validation of others. Some studies suggest that the effectiveness of noninvasive methods for assessing liver fibrosis may increase when they are combined, and a number of sequential and synchronous algorithms have been proposed for this purpose, with the aim of reducing rather than substituting liver biopsies. This may represent a rational and reliable approach for implementing noninvasive assessment of liver fibrosis in clinical practice. It could allow more comprehensive first-line screening of liver fibrosis in hepatitis C than would be feasible with liver biopsy alone.     

Prospective comparison of transient elastography,point shear wave elastography,APRI and FIB‐4 for staging liver fibrosis in chronic viral hepatitis

Ultrasound‐based elastography and serum indexes have been individually validated as noninvasive methods for staging liver fibrosis in chronic viral hepatitis. We aimed to compare the accuracy of transient elastography (TE), shear wave elastography (SWE), aspartate aminotransferase to platelet index (APRI) and Fibrosis‐4 index (FIB‐4) with the METAVIR liver fibrosis staging in viral hepatitis patients. We enrolled 121 treatment‐naïve chronic hepatitis B and C monoinfected patients. All underwent liver biopsy had biochemistry tests and liver stiffness measurements by TE using M and XL probes followed by point SWE performed on the same day. The accuracy of each method for predicting different fibrosis stages was demonstrated as an area under the receiver operating characteristic (AUROC) curves. The AUROCs of TE using M and XL probes, SWE, APRI and FIB‐4 were 0.771, 0.761, 0.700, 0.698 and 0.697, respectively, for significant fibrosis; 0.974, 0.973, 0.929, 0.738 and 0.859, respectively, for advanced fibrosis; and 0.954, 0.949, 0.962, 0.765 and 0.962, respectively, for cirrhosis. TE using the M probe was comparable to the XL probe in detecting all fibrosis stages. TE was superior to SWE for assessing significant fibrosis and advanced fibrosis. For cirrhosis, the performances of TE, SWE and FIB‐4 were similar. APRI was least accurate in liver fibrosis staging. To conclude, for patients with viral hepatitis, TE using either M or XL probe is an effective noninvasive test for assessing liver fibrosis, particularly advanced fibrosis and cirrhosis, while SWE and FIB‐4 possess an excellent accuracy in predicting cirrhosis.     

Elastography in hepatology.

A common characteristic of all chronic liver diseases is the occurrence and progression of fibrosis toward cirrhosis. Consequently, liver fibrosis assessment plays an important role in hepatology. Besides its importance for prognosis, determining the level of fibrosis reveals the natural history of the disease and the risk factors associated with its progression, to guide the antifibrotic action of different treatments. Currently, in clinical practice, there are three available methods for the evaluation of liver fibrosis: liver biopsy, which is still considered to be the 'gold standard'; serological markers of fibrosis and their mathematical combination - suggested in recent years to be an alternative to liver biopsy - and, more recently, transient elastography (TE). TE is a new, simple and noninvasive method used to measure liver stiffness. This technique is based on the progressing speed of an elastic shear wave within the liver. Currently, there are only a few studies that have evaluated TE effectiveness in chronic liver diseases, mostly in patients infected with the hepatitis C virus. Further studies are needed in patients with chronic liver disease, to assess the effectiveness of the fibrosis treatment.     

The use of transient elastography in the management of chronic hepatitis B

There has been increasing interest in noninvasive methods of assessing liver fibrosis over the last decade. The use of transient elastography in measuring liver stiffness has become the forefront of a wide range of noninvasive tools. Most of the other methods are based on measurements of biomarkers associated with fibrosis. There are several reasons for its wide acceptance, including the ease of performing a scan, the short procedure time, the results being immediately available on completion of the examination, and its reproducibility. For chronic hepatitis B (CHB), the cut-off values for F3 and F4 fibrosis range between 7.5–12.0 and 11.0–13.4 kPa, respectively, although the cut-offs may be slightly lower in those with normal ALT. In addition to measuring liver fibrosis, recent studies have demonstrated several other roles for transient elastography, including selecting patients who will benefit from antiviral therapy, monitoring response to antiviral therapy, and predicting long-term outcomes. However, there are limitations associated with transient elastography, including the confounding effects of inflammatory activity, and to a lesser extent, steatosis, on liver stiffness. There is also reduced accuracy observed in lower fibrosis stages (F0–F2). Furthermore, the incidences of failed and unreliable scan have been reported to be ~ 3 and 16%, respectively. Although liver biopsy can be avoided in an estimated 50–60% using transient elastography, in situations where liver stiffness measurement is nondiagnostic or inconsistent with the clinical picture, a biopsy is still recommended. Further studies are needed to consolidate the role of transient elastography in the management of CHB, and for incorporation of this method into current treatment guidelines.     

Non-invasive assessment of liver fibrosis:Between prediction/prevention of outcomes and cost-effectiveness

The assessment of the fibrotic evolution of chronic hepatitis has always been a challenge for the clinical hepatologist. Over the past decade, various noninvasive methods have been proposed to detect the presence of fibrosis, including the elastometric measure of stiffness, panels of clinical and biochemical parameters, and combinations of both methods. The aim of this review is to analyse the most recent data on non-invasive techniques for the evaluation of hepatic fibrosis with particular attention to costeffectiveness. We searched for relevant studies published in English using the Pub Med database from 2009 to the present. A large number of studies have suggested that elastography and serum markers are useful techniques for diagnosing severe fibrosis and cirrhosis and for excluding significant fibrosis in hepatitis C virus patients. In addition, hepatic stiffness may also help to prognosticate treatment response to antiviral therapy. It has also been shown that magnetic resonance elastography has a high accuracy for staging and differentiating liver fibrosis. Finally, studies have shown that non-invasive methods are becoming increasingly precise in either positively identifying or excluding liver fibrosis, thus reducing the need for liver biopsy. However, both serum markers and transient elastography still have "grey area" values of lower accuracy. In this case, liver biopsy is still required to properly assess liver fibrosis. Recently, the guidelines produced by the World Health Organization have suggested that the AST-to-platelet ratio index or FIB-4 test could be utilised for the evaluation of liver fibrosis rather than other, more expensive non-invasive tests, such as elastography or Fibro Test.     

Is liver biopsy still needed in children with chronic viral hepatitis?

Liver biopsy is a standard method used for obtaining liver tissue for histopathological evaluation. Since reliable serological and virological tests are currently available, liver biopsy is no longer needed for the etiological diagnosis of chronic hepatitis B and C. However, liver histology remains the gold standard as a prognostic tool, providing information about the liver disease progression(grading of necroinflammatory activity and staging of fibrosis) and serving clinicians in the management and therapeutic decisions. In general, histopathological evaluation is indicated before starting the antiviral treatment. Main limitations of the liver biopsy include its invasive and painful procedure, sampling errors and the inter- and intra-observer variability. In addition, indications for the liver biopsy in pediatric patients with chronic viral hepatitis were questioned recently, and efforts have been made toward the development of non-invasive methods as an alternative to the liver biopsy. The most commonly used methods are novel imaging studies(elastography) and combinations of biomarkers. However, to date, none of these tests was validated in children with chronic viral hepatitis. In this review, we present the current status of the liver biopsy in the management of chronic viral hepatitis B and C in pediatric population, including specific indications, complications, contraindications, problems, limitations, and alternative non-invasive methods.     

Non‐invasive assessments for liver fibrosis: The crystal ball we long for

Non‐invasive assessment of liver fibrosis has been one of the most rapidly advancing fields in hepatology in the last decade. Progressive liver fibrosis results in cirrhosis, hepatocellular carcinoma (HCC), and various liver‐related complications in essentially all chronic liver diseases. Assessment of liver fibrosis allows clinicians to determine the prognosis, need of treatment, disease progression, and response to treatment in patients with chronic liver disease. Liver biopsy has been the gold standard in last few decades and most adopted diagnostic tool in clinical trials. Nonetheless, it is impractical to apply the test in a large number of patients or to do it serially. Hence, various non‐invasive assessments have been developed and adopted in some international management guidelines. Liver stiffness measurement (LSM) with transient elastography is one of the most widely validated non‐invasive assessments for liver fibrosis. It is an accurate and reproducible method to predict advanced fibrosis in chronic hepatitis B. Using transient elastography, it is possible to perform repeated liver fibrosis assessments on a large number of asymptomatic patients. The key challenge of his tool is the confounding effect of alanine aminotransferase (ALT) level, such that decrease in LSM may only reflect ALT normalization, hence not accurate enough to indicate regression of liver fibrosis. This may be partially handled by combining LSM with a serum‐based formula, which is independent of ALT such as the Forns index and enhanced liver fibrosis test. An LSM‐based HCC risk score is useful to prioritize patients for HCC surveillance.